1. Field of the Invention
The present invention relates to a composition for preventing, alleviating or treating obesity comprising partial fragments of Tat (Trans activator of transcription).
2. Background of Technique
Wasting is a major cause of morbidity and mortality associated with Acquired Immunodeficiency Syndrome (AIDS). The present inventors investigated whether Trans activator of transcription (Tat), a protein encoded by the Human Immunodeficiency Virus 1 (HIV-1) genome, is one of the etiological agents of wasting Tat was found to have a profound effect on the reduction of adipose tissue mass and adipocyte cell size in rabbits, obese Lep−/− mice, and transgenic mice overexpressing Tat, thus demonstrating Tat's involvement in wasting. Central and peripheral administration of Tat suppressed food intake but increased thermogensis, oxygen consumption, fatty acid oxidation, and locomotor activity. Central administration of a Tat (a.a. 1-72) and Tat fragments (a.a. 20-45; a.a. 20-57) induced anorexia and weight loss. The resent inventors also mapped the domain of Tat important in weight or fat tissue reduction to a.a. 20-45. These findings suggest that Tat protein fragments can cause wasting similar to that observed in AIDS patients through increase in energy expenditure and reduction in food-intake (anorexia).
Human Immunodeficiency Virus-1 (HIV-1) is the etiological agent for Acquired Immunodeficiency Syndrome (AIDS). There are more than 40 million people infected with the HIV virus worldwide (Myers et al., 1996). Metabolic disturbances, weight loss, anorexia, and the breakdown of body tissue are major clinical consequences of HIV infection. These changes, collectively called wasting, are some of the most devastating aspects of AIDS, and are a major cause of morbidity and mortality in AIDS patients (Grunfeld et al., 1992a, b; Macallan et al., 1993, 1995).
Among the multiple mechanisms proposed, two changes that are thought to significantly contribute to wasting are an increase in resting energy expenditure and anorexia (Grunfeld et al., 1992a, b; Macallan et al., 1993). It has been suggested that these metabolic changes are mediated by the increase in cytokine levels triggered by bacterial infection (Abad et al., 2002; Grunfeld et al., 1991 and references therein; Plata-Salaman et al., 1994; Puigserver et al., 2001), but the critical candidate causing wasting in HIV-1-infected patients is unknown. Another important regulator of food intake and energy expenditure is leptin (Friedman et al., 1998). However, it was reported that serum leptin levels in patients with AIDS who were experiencing decreased food intake and weight loss, were indistinguishable from control levels (Grunfeld et al., 1996; Yarasheski et al. 1997). This result suggested that anorexia and wasting in AIDS patients is unrelated to leptin. The presence of the HIV Nef protein in the nucleus suppressed PPAR gamma expression and reduced fatty acid levels in human T and macrophage cell lines (Otake et al., 2004). Although Nef was tested in these two cell lines, the role of Nef in increased resting energy expenditure and anorexia is unknown.
Though it has been suspected that the wasting observed in HIV-1-infected patients might be related to metabolic disturbances, such as anorexia and the increased resting energy expenditure caused by the HIV-1 infection and a secondary illness, no direct causal link between HIV and metabolism has been identified (Grunfeld et al., 1992a, b; Macallan et al., 1993). In order to understand the molecular mechanism of wasting, and to develop a therapeutic method against wasting, it is important to identify the etiological agents of the process. It was assumed that the etiological agent of wasting was probably one of the viral proteins encoded by the HIV-1 genome, because infection with HIV-1 and subsequent viral replication eventually lead to wasting.
Tat is a small nuclear transcriptional activator protein encoded by the HIV-1 genome and its primary structure (amino acid sequence) is conserved in genomes of all primate lentiviruses (Myers et al., 1996). Tat is one of the most important regulators of transcription and replication of HIV-1, and plays a primary role in regulating productive and processive transcription from the HIV-1 long terminal repeat (LTR). Although full-length Tat is composed of 101 amino acids, a 72-amino-acid truncated version of Tat is sufficient to carry out most of the biological functions of full-length Tat (Jeang et al., 1999 and references therein). Tat has been shown to have multiple intracellular biological activities, such as T-lymphocyte activation, cell apoptosis, and the modulation of cellular gene expression. In addition, Tat exits from infected cells via a leaderless secretory pathway (Chang et al., 1997) and functions as an extracellular chemokine and growth factor (Jeang et al., 1999 and references therein).
Throughout this application, various publications and patents are referred and citations are provided in parentheses. The disclosures of these publications and patents in their entities are hereby incorporated by references into this application in order to fully describe this invention and the state of the art to which this invention pertains.